1997 Outlook

by John S. James

In 1996 HIV treatment advanced far more than in any other
year yet of the epidemic. But no one knows whether or how
much this improvement will continue.

In the most important measure, reduction in deaths,
statistics beginning to emerge suggest a drop in the death
rate by at least half in the past year, in diverse
populations which are receiving modern treatment.

* In San Francisco, the total number of obituaries received
by the BAY AREA REPORTER -- almost all due to AIDS-related
deaths -- dropped by at least half between the beginning and
the end of 1996. And the January 1996 rate was already much
lower than the peak, which occurred several years before.
(For more information, see AIDS Treatment News #260, December
6, 1996.)

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* The California Medical Facility in Vacaville, California,
which treats most male prisoners in California who have
serious medical conditions, had far fewer deaths at its in-
prison hospice (when we spoke there for World AIDS Day, in
early December 1996) than a year before. We do not have final
figures for the year, but as of December 6 it appeared that
the total deaths for the year would be reduced at least by
half. The CMF is a leader in HIV/AIDS treatment in prison;
combination antiretroviral treatment including at least one
protease inhibitor (ritonavir) is used there.

* The best data so far is from a study in British Columbia,
Canada, which found that the death rate for that province in
the last three months of 1996 was only one third what it was
two and a half years ago. Julio Montaner, M.D., of the B.C.
Centre for Excellence in HIV/AIDS, attributed the reduction
to improved treatment. The study has not yet been formally
published, but was confirmed by the researchers after it was
obtained by the media (see TORONTO STAR, January 8, page A2).

The fact that similar results occurred in very different
populations who all had access to modern HIV care -- in
addition to anecdotal reports of even greater reductions of
deaths in medical practices specializing in HIV -- strongly
suggests that this large and unexpected decrease is not due
to the natural history of the epidemic. Improved treatment is
almost certainly the main reason.

Also, all of the treatment effect on deaths in 1996 must have
been in persons with advanced illness (which is hardest to
treat in any disease) -- since those with early HIV infection
or only moderate progression early in 1996 would not have
died in that year anyway. The new treatments might work even
better in those who start them earlier. (But no one knows for
sure, since it would take years to measure survival
improvement due to early treatment of HIV disease -- if
meaningful data can be obtained at all, which is unlikely,
since most patients would change treatments during the years
it would take to run such a study).

But despite the great decrease in deaths during the last
year, AIDS experts are cautious and guarded in their
optimism. Anecdotally there are many reports of failures of
the new anti-HIV drug "cocktails" -- either because the virus
develops resistance to the drugs, or because the patient
becomes unable to tolerate continued treatment and the virus
returns after one or more drugs are stopped. And many
patients (most estimates range between 10 and 30 percent)
cannot be successfully treated with the new drugs even
initially, for various reasons. As would be expected, the
treatments are most likely to work in those with relatively
early disease, and in those who have had little or no prior
treatment with any of the drugs in the combination which is
being used. Historically, the drugs have become available one
by one (for many years there was only AZT), so the virus
populations in many patients had a chance to become resistant
to the drugs one after the other.

And the great majority of people with HIV around the world,
including many in the U.S., do not have access to medical
care from HIV-experienced physicians, nor access to the drugs
they may need. A recent article in a European newsletter
noted that most patients in Estonia die within weeks of an
AIDS diagnosis, and the main AIDS organization there had just
seen its first case of survival for one year after diagnosis
("Countries: AIDS in Estonia," EUROPEAN AIDS Treatment News,
volume 5, number 5, pages 96-99). Even in the UK, it was
recently reported that persons with HIV are only half as
likely to receive modern combination treatments as in other
counties, due to funding problems. And in the U.S., quality
of care varies greatly by social class, and by region.

Even with access to the best care, no one knows for sure if
the great improvements for some groups in 1996 will be
permanent. Will deaths continue to decrease, or will 1996 be
looked back on as an exception? The answer will depend
greatly on what we do now -- which is why the"end of AIDS"
media message is so dangerously misleading. The treatments we
have must be used carefully -- and continued research and
development not only remain essential, but have more
opportunities now than ever before to save lives.

Upcoming Retroviruses Conference

Next week we will attend the 4th Conference on Retroviruses
and Opportunistic Infections, the most important AIDS
research meeting in 1997. It is difficult to learn much in
advance about what will be presented (abstract books and
abstracts on disks are being sent, but no copies were
available until the day this issue went to press). We do not
expect major surprises, but there will certainly be
important, in-depth information in most areas of AIDS
treatment development, which we will cover in future issues.
(See &quot Retroviruses Conference: Where to Find Reporting on the
Internet," below, for suggestions on how to follow the
conference if you cannot attend.)

1997: Protease Inhibitors

* An overview of the currently available protease inhibitors
(indinavir, nelfinavir, ritonavir, and saquinavir), by AIDS
experts at San Francisco General Hospital and elsewhere,
appeared in JAMA (THE JOURNAL OF THE AMERICAN MEDICAL
ASSOCIATION), January 8. The full text is available on the
American Medical Association's Web site, at:

* Nelfinavir (VIRACEPT(R)) is a protease inhibitor now
available to some patients through an expanded access
program; it could be approved for general availability early
this year. It appears to have fewer side effects than the
currently-approved protease inhibitors, and a somewhat
different viral resistance pattern (which might improve its
usefulness for patients already resistant to one or more of
the other protease inhibitors). For more information on
nelfinavir, see the article below.

* An important focus of research will be treatment failures
with protease inhibitors. How long will high-level viral
suppression last -- and in which patients? What treatments
are best for patients who have failed one or more protease
inhibitor regimens?

* Another research focus will be blood tests to determine
which drugs a patient's virus is resistant to. Some such
tests are already available to physicians, but they are still
far from official approval or widespread routine use.

1997: Other Antiretrovirals

* 1592. 1592 (1592U89), being developed by Glaxo Wellcome and
now in early clinical trials, is a nucleoside analog drug (in
the same general class as AZT), but is much more effective
than AZT in suppressing HIV. 1592 has good penetration across
the blood-brain barrier; it is also important because it is a
new option for persons whose virus already became resistant
to AZT or other current drugs. Because of the schedule of
clinical trials, 1592 is not expected to be approved in 1997.
Activists are seeking a pre-approval expanded-access program,
especially for those with no other treatment options, with
wider access as more safety data becomes available from the
trials (see "1592: Consensus Letter on Access to New Glaxo
Drug, AIDS Treatment News #261, December 20, 1996).

* Integrase inhibitors. This is a new class of anti-HIV
drugs, which target a different viral enzyme than the
protease inhibitors or the nucleoside analog drugs target;
therefore, virus which has already developed resistance to
the previous drugs would not be expected to have any cross-
resistance to integrase inhibitors. There has been concern
for years that large companies have been less diligent in
developing integrase inhibitors than they were with other
classes of drugs, resulting in a lack of treatments in the
pipeline after the protease inhibitors. Government
researchers screened a number of chemicals as potential
integrase inhibitors and published the results in early 1993
(Fesen, MR and other, "Inhibitors of Human Immunodeficiency
Virus Integrase," PROCEEDINGS OF THE NATIONAL ACADEMY OF
SCIENCE, U.S.A., March 1993, pages 2399-2403), but government
agencies alone almost never develop drugs in the U.S. Only
one integrase inhibitor is in human trials, as far as we
know; it is Zintevir(TM) (also known as AR 77), being
developed by Aronex Pharmaceuticals, Inc.

* Drugs with new targets. The recent discovery of additional
receptors (besides CD4), which HIV uses in addition to CD4 in
order to enter a cell, has provided new targets for
antiretroviral drug design.

Also, at least one drug which targets the zinc fingers of HIV
is now in human trials.

* PMPA, being developed by Gilead Sciences, is another
antiretroviral worth watching. After promising results in
animal studies, a human trial has been started.

* The list above is not complete, as there are many other
potential antiretrovirals in various stages of research.

Other Treatments

Due to limited time and limited space in this issue, we
cannot cover many other classes of treatments, including
immune-based treatments, immune reconstitution, therapeutic
or preventive vaccines, and various cytokine approaches.

Some areas that we think need more attention include:

* A major problem in researching immune-based treatments has
been the practical difficulties in doing immune function
tests, including control of laboratory errors. More research
is needed on developing flow cytometry tests for immune
function (using similar technology as now used for measuring
CD4 counts), because these tests usually are easy to perform,
and greatly reduce the opportunities for laboratory error.

* More attention is also needed for potential treatments now
often classified as "alternative" or "complementary" -- such
as NAC, glutamine, or DHEA. Treatments become "alternative"
because people can obtain them now, despite lack of official
approval -- which strongly correlates with them being largely
or completely nonproprietary, meaning that there is little
incentive for formal research. Alternative/complementary
treatments are much less effective as antiretrovirals than
the mainstream drug "cocktails" available today -- but they
may have other uses, such as the possibility that NAC might
reduce the problem of abnormal sensitivity to co-trimoxazole
(Bactrim, Septra) by persons with HIV. Certain nutritional
treatments might reduce drug side effects, increase
absorption of drugs by certain patients, or otherwise improve
general health or quality of life. Since the mainstream drug-
development system will not give this work the attention it
deserves, due to the relative lack of financial incentives,
the community needs to be involved.

Access Issues, Compliance, Standards of Care

These areas will become even more important this year. We
cannot review them here, except to mention just a few of the
areas that need to be watched:

Recently the AIDS Action Council has warned about Clinton
Administration proposals to save money by restricting
Medicaid -- which pays for care for 53% of adults and 90% of
children with HIV or AIDS. There is particular concern about
a "per capita cap" or maximum Federal payment per Medicaid
beneficiary. People with HIV could be disproportionately
affected by the resulting state restrictions on care.

Private insurance issues include a growing use of much
higher co-pay amounts for persons who need expensive drugs.
On the other hand, a new Federal law, which will become
effective in mid year, will make it easier to move from one
group health insurance to another, without being excluded for
prior conditions.

Improvement in AIDS/HIV treatment -- to the extent that it
is sustained and extended -- will continue to raise issues of
the division of resources between drugs and services. More
importantly, improved treatment will require all AIDS
organizations to re-evaluate their work, and plan how it
should or should not change in the new environment.

Nelfinavir: Agouron Announces Expanded Access for Children, a Major New Trial, and Enlarged Expanded Access for Adults

The protease inhibitor nelfinavir (VIRACEPT(R)) is not yet
approved for marketing, but is available to some patients
through an expanded access program. Nelfinavir may have fewer
side effects than the currently approved protease inhibitors.

On January 6 the drug's developer, Agouron Pharmaceuticals,
Inc. of La Jolla, California, announced that it will make
nelfinavir available "without charge to any HIV-infected
child [ages 2-13 years] until the drug is approved for
marketing in the United States." Safety trials have been run
in children, and are expected to be presented next week at
the 4th Conference on Retroviruses and Opportunistic
Infections. Agouron has developed an oral powder formulation
for children, while it was developing the tablets for adults.

So far no protease inhibitor has been available for children,
outside of small trials, because dosage and safety studies
had not been completed.

Physicians, health-care professionals, and parents interested
in the VIRACEPT Pediatric Expanded Access Program can call
the VIRACEPT Expanded Access Program Hotline, 800/621-7111,
Monday through Friday from 8:00 a.m. to 6:00 p.m. Eastern
time.

* On January 6 Agouron announced a large clinical trail to
compare nelfinavir plus nucleoside analogs (AZT, 3TC, ddI,
ddC, d4T) vs. ritonavir (Norvir(R)) plus nucleoside analogs.
1300 persons with CD4 count under 100 will be randomly
assigned to one or the other treatment. This trial will be
run by the CPCRA, an AIDS research program of the U.S.
National Institute of Allergy and Infectious Diseases, and
the Canadian HIV Trials Network. It seems to be well regarded
by treatment activists, because both treatment arms are
appropriate therapy, with neither designed to likely be
weaker than the other.

For information on enrolling in this trial, call the AIDS
Clinical Trials Information Service, 800/TRIALS-A.

* On January 8 Agouron relaxed the entry criteria for its
expanded access program for adults (age 13 and older).
"People will now qualify for the VIRACEPT Expanded Access
Program if they are unable to take indinavir (Crixivan(R))
and/or ritonavir due to intolerance or prior failure and who
have had CD4+ T-cell counts of less than or equal to 100
cells/mm3 during any past medical examination." Previously it
was necessary to be unable to use all three approved protease
inhibitors, and to have a CD4 count under 50. For information
on this program, call the VIRACEPT Expanded Access Program
Hotline, 800/621-7111, Monday through Friday from 8:00 a.m.
to 6:00 p.m. Eastern time.

* On December 23 Agouron announced that it had applied to the
FDA for approval to market nelfinavir in the U.S. The company
is applying under the FDA's accelerated approval regulations
for both the adult tablets and the pediatric powder
formulations. These regulations allow approval based on
blood-test results such as viral load, but require large
human trials later to prove clinical benefit.

Retroviruses Conference: Where to Find Reporting on the Internet

The 4th Conference on Retroviruses and Opportunistic
Infections will take place January 22-26 at the Sheraton
Washington Hotel. Abstracts, reports (either daily, or after
the conference), and audio feed and slide images, will be
available through various sites on the Internet. You may want
to check the following sites, which are accessible without
charge, and from anywhere in the world.

* Audio feed, slides, and abstracts: The conference
organizers will broadcast (on the Internet) audio and slides
of some of the major sessions of the conference, about 12
hours after the presentations. The equipment needed is a
modem (with a DOS/Windows computer, either a 14.4 or 28.8
modem can be used; with a Macintosh, 28.8 is required), and a
sound card. The system is optimized for either Netscape
Navigator or Microsoft Internet Explorer, but other browsers
may work as well. Users will see a picture of the presenter,
with the slides changing with the talk as if one were in the
room, and hear the audio (using RealAudio software, which can
be downloaded through the site). There will also be a search
engine to help skip ahead in a talk.

This system will be accessible through
www.retroconference.org. The conference abstracts will be
available through the same site; note that most abstracts
were submitted months ago and have not been revised, but that
the "late breaker" abstracts are new. (The "idsociety" Web
address for the abstracts, which we published in our last
issue, is being changed to the"retroconference" address,
above; as we go to press on January 14, the "idsociety"
address only has news and abstracts of LAST YEAR'S 1996
Retroviruses conference, and the "retroconference" address is
not yet available. If you have problems connecting to the
"retroconference" address, check the other sites for the
latest information, or call AIDS Treatment News.)

The conference organizers hope to broadcast the State of the
Art talks, the two opening sessions, and one symposium each
afternoon. It may not always be possible to get permission
from the presenters, however, because medical journals often
consider Internet distribution to be "publication," meaning
that they will refuse to publish an article if the
information has been released that way.

Check the "retroconference" site for the latest information.

* As we announced in our last issue, Healthcare
Communications Group has organized 16 authors and writers to
produce daily reports on the Retroviruses conference, to be
available the following morning. Check their site at
http://www.healthcg.com -- which already has useful pre-
conference summaries on pathogenesis, viral markers,
antiretrovirals, immunomodulation, TB/MAC, CMV, fungal
infections, and AIDS-related cancers.

* The Body, an organization which provides AIDS information
on the Web, will publish reports by Ramon A. (Gabriel)
Torres, M.D., Director of the AIDS Center at St. Vincent's
Hospital in New York, and Andy Pavia, M.D., Director of
Clinical Research for the University of Utah Health Sciences
AIDS Center. Coverage will include a question and answer
session with Drs. Torres and Pavia. The Web site is
http://www.thebody.org.

* The International Association of Physicians in AIDS Care
will have daily reports by technical writers Mark Mascolini
and David MacDougall, at http://www.iapac.org.

* Extensive reports of the conference will be published on
the Critical Path AIDS Project site, http://www.critpath.org.

* Jules Levin will report on protease inhibitors on
http://www.aidsnyc.org/natap.

* Also, there will be many wire service and other news-media
reports on the Retroviruses conference. An excellent free
source for most AIDS-related daily news is the AIDS list of
AEGIS (AIDS Education Global Information System), run by
Sister Mary Elizabeth in Southern California. You only need
an email address to use this service; you do not need access
to the World Wide Web. To subscribe, send email to:
majordomo@global.org, with the message:

subscribe aids
end

Note: This service sends about 15 to 20 AIDS-related news
reports per day (and probably more during the Retroviruses
conference). If you want to reduce email traffic, you can
have the messages collected into a digest, which is sent when
it reaches 40,000 characters in size. To receive the digest,
send email to: majordomo@global.org, with the message:

subscribe aids-digest
end

For more information about this AIDS mailing list, send the
message "info aids ", or "info aids-digest " (without the quote
marks) to: majordomo@global.org. Or see the AEGIS home page,
http://www.aegis.com.

Note: By agreement with the International Association of
Physicians in AIDS Care, AEGIS will also send to its AIDS
mailing list the Retroviruses conference reports published on
the http://www.iapac.org Web site described above.

AIDS Treatment News has obtained a 126-page draft report of a
major toxicology study of THC, the main psychoactive
ingredient of marijuana. The study was completed over two and
a half years ago, and passed peer review for publication, but
has been kept quiet until this month, when someone leaked
copies of the draft report. As far as we know, the public has
never been told about this research -- for example, the drug-
reform movement seems not to have known about its existence.
This work may have been hushed because its findings are not
what the drug-war industry would want.

The study gave huge doses of THC to rats and mice by stomach
tube, and looked for cancers and other evidence of toxicity.
First there were small toxicity studies, which used enough
THC to kill some of the animals; later, two-year studies were
run in both rats and mice, using doses which were still much
higher than those of marijuana smokers. The two-year studies
tested THC in several hundred rats and several hundred mice.

In rats, those given THC had a clear survival advantage over
the untreated controls; this effect was statistically
significant in all dose groups, and in both males and
females. In mice (which were given much larger doses than the
rats relative to body weight) there was no survival
difference among the groups -- except that those given the
highest dose (which was close to the lethal dose for mice)
had worse survival.

In both mice and rats, in both males and females, "the
incidence of benign and malignant neoplasms ... were
decreased in a dose-dependent manner" -- meaning that the
more THC the animals were given, the fewer tumors they
developed.

The treated animals weighed less than the controls (even
though both ate about the same amount of food); the
researchers speculated that the lower body weight may have
partly accounted for the increased survival and reduced
tumors in the THC-treated animals.

The doses were large enough to cause seizures and convulsions
in many of the animals, especially when they were dosed or
handled. These did not start immediately, but after many
weeks, depending on the dose. The researchers looked for
brain lesions in animals which had seizures, but found none.

No evidence of carcinogenic activity in the rats, but there
was "equivocal evidence" of one kind of thyroid tumor in the
mice -- with no evidence of a dose-dependent response. Other
tumors were less common in the treated animals than in the
controls -- except in one case, which the toxicologists
believed was due to the fact that the treated animals lived
longer, and therefore had more opportunity to develop tumors.

The report includes a professionally objective review of the
biological effects, possible toxicities, and possible medical
uses of THC and marijuana.

The title of the report is "NTP Technical Report on the
Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)-
Tetrahydrocannabinol (CAS No. 1972-08-3) in F344/N Rats and
B6C3F(1) Mice (Gavage Studies)." Over 35 researchers
contributed to this study, and 12 others reviewed their work;
several institutions, including the National Toxicology
Program and SRI International, were involved. The document we
received is report NTP TR 446, NIH Publication No. 94-3362,
of the U.S. Department of Health and Human Services. ("NTP"
stands for National Toxicology Program, which is made up of
four Federal agencies within Health and Human Services.) Each
page of the draft is stamped "not for distribution or
attribution." In addition to the 126-page document we have
reviewed here, there are 11 appendices, which we have not
seen.

According to the draft, the report will be available from NTP
Central Data Management, 919/ 541-3419. AIDS Treatment News
requested a copy of the final report when it is ready, and
also requested a copy of the draft. Now that the existence of
the report has become publicly known, we have heard that
draft copies are being sent if requested -- despite the
notice on each page not to distribute them.

Comment

It would be wrong to interpret this study as showing a
beneficial or protective effect of marijuana. The animals
were given very large doses, resulting in substantially lower
body weight, which may itself have caused much of the
survival and tumor improvements. Also, this study used THC,
not marijuana smoke -- which like any smoke contains many
chemicals, some of which are likely to be harmful.

But the study does provide strong evidence that there is no
significant cancer risk (if any at all) from the main
psychoactive ingredient of marijuana; any such risk would be
from incidental substances in the smoke. And if there is such
a risk, the modern high-potency marijuana would likely reduce
it, by reducing the amount of smoke required to obtain the
desired effect.

Also, there is no known case of any human death from overdose
of marijuana or THC, or from any other acute toxicity of
these substances -- a remarkable safety record, compared with
alcohol, aspirin, or many other common drugs. (The toxicology
report does not say there have been no deaths, but the
authors listed none, after doing an exhaustive survey of the
literature.)

The literature review on the effects of THC and marijuana
shows how medical research has been politically skewed
(although the paper itself does not state this point). There
are almost no studies of possible medical uses of marijuana,
but many studies looking for possible harm. Any positive
findings, therefore, can be used to support the drug war --
while negative findings (those which fail to show any effect)
are usually ignored. Although many doctors and patients have
reported important medical benefits, scientific studies of
medicinal use have seldom been allowed to happen, since
positive findings could challenge the official public-
relations tactic of demonization. The drug war itself has
controlled the medical research agenda, since it controls
legal access to marijuana. Like most permanent wars, it
strives for self preservation.

The newly available Federal toxicology study provides the
best evidence yet that the risks of THC are small. What other
drug would increase life expectancy of rats when given in
huge overdoses daily for two years? The recent Federal
attacks on medical marijuana -- against doctors and
desperately ill patients -- are needlessly cruel, and
bizarrely inappropriate to scientific and medical
understanding.

Activist Groups and PWA Coalitions, U.S. and Canada

Updated January 1997

Since 1990 AIDS Treatment News has published a list of ACT UP
or activist groups, PWA coalitions, and buyers' clubs; this
year the buyers' clubs were listed separately (issue #260,
December 6, 1996). We called the numbers below and included
only those we could verify; some are home telephones, not
offices. Within states, the listings are alphabetical by
city.

For information about ACT UP affiliates, call the ACT UP
Network, 215/731-1844. For information about other PWA
organizations, call the National Association of People with
AIDS (NAPWA), 202/898-0414. If you know of other
organizations which should be listed in this directory,
please call AIDS Treatment News at 800/TREAT-1-2, or 415/255-
0588.

There are well over ten thousand AIDS organizations in the
U.S. alone; only a few can be included in this specialized
list. To find out about services and organizations in your
area, call the National AIDS Hotline, 800/342-AIDS, 24 hours
a day; for the same information in Spanish, call 800/344-
SIDA, 8 a.m. to 2 a.m. Eastern time, 7 days a week.

Albany ACT UP/Albany 518/861-6337
Long Island PWA Coalition 516/225-5700
New York City ACT UP/New York 212/642-5499
New York City AIDS Treatment and Data Network
800/734-7104, or 212/260-8868
New York City Housing Works, Inc. 212/966-0466
New York City Lesbian AIDS Project 212/337-3532
New York City Mothers' Voices 800/342-6705
New York City National AIDS Treatment Advocacy
Project (NATAP) 212/219-0106
New York City New York AIDS Coalition 212/629-3075
New York City PWA Coalition of New York
800/828-3280, or 212/647-1415
New York City Stand Up Harlem 212/926-4541
New York City Treatment Action Group (TAG) 212/260-0300
New York City Treatment and Data Committee
of New York 212/929-4952

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